Oscar Colegio, MD, PhD is an Assistant Professor of Dermatology at Yale University whose career goal is to become an independent investigator with expertise in the tumor immunology of skin cancers. He has developed model systems to study the role of macrophages, cells of the innate immune system, in tumor progression under the guidance of Ruslan Medzhitov, PhD. Dr. Colegio's clinical interest in immunodeficiency-associated skin cancers is complementary to his basic research interests. He directs the Yale Transplant Dermatology Clinic, the only clinic in Connecticut dedicated to post-transplant skin screenings and the primary setting for enrolling subjects for the proposed studies. More than 500,000 people have received a transplanted organ in the United States and 27,000 additional transplants are performed each year. Solid organ transplant recipients are 100-times more likely to develop cutaneous squamous cell carcinomas (SCCs) than the general population. As immunosuppression used after transplantation focuses on impairing T cell activation, a majority of studies on the etiology of post-transplant skin cancers has focused on the loss of cancer immunosurveillance. However, we have recently determined that the innate immune system is also critical in tumorigenesis. Further, increased numbers of macrophages present near tumors correlate with poor prognoses in ~80% of tumors. To date, few studies have characterized the mechanistic role of macrophages in the progression of SCCs. We have developed in vitro and murine model systems to screen and verify soluble tumor-derived factors that activate macrophages to become tumor promoting. Our objectives are to identify and verify tumor-promoting factors produced by tumor-associated macrophages isolated from human SCCs. Characterizing the core elements of these tumor-promoting pathways is critical to identifying targets and abrogating them to prevent tumor progression and metastasis of SCCs. The Yale University Departments of Immunobiology and Dermatology together have extensive scientific and clinical resources, which will enable the successful achievement of the proposed aims. Dr. Colegio will design and perform the proposed experiments under the primary mentorship of a pioneer in innate immunity, Ruslan Medzhitov, PhD, and advisory guidance of a physician scientist with expertise in SCCs, Michael Girardi, MD. In sum, this proposal will define critical components of tumor immunology while preparing the applicant for a successful independent research career as a physician scientist.